Spleen tyrosine kinase (SYK) is a 72 kDa non-receptor cytoplasmic tyrosine kinase. SYK has a primary amino acid sequence similar to that of zeta-associated protein-70 (ZAP-70) and is involved in receptor-mediated signal transduction. The N-terminal domain of SYK contains two Src-homology 2 (SH2) domains, which bind to diphosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) found in the cytoplasmic signaling domains of many immunoreceptor complexes. The C-terminus contains the catalytic domain, and includes several catalytic loop autophosphorylation sites that are responsible for receptor-induced SYK activation and subsequent downstream signal propagation. SYK is expressed in many cell types involved in adaptive and innate immunity, including lymphocytes (B cells, T cells, and NK cells), granulocytes (basophils, neutrophils, and eosinophils), monocytes, macrophages, dendritic cells, and mast cells. SYK is expressed in other cell types, including airway epithelium and fibroblasts in the upper respiratory system. See, e.g., Martin Turner et al., Immunology Today (2000) 21(3):148-54; and Michael P. Sanderson et al., Inflammation & Allergy-Drug Targets (2009) 8:87-95.
SYK's role in ITAM-dependent signaling and its expression in many cell types suggest that compounds which inhibit SYK activity may be useful for treating disorders involving the immune system and inflammation. Such disorders include Type I hypersensitivity reactions (allergic rhinitis, allergic asthma, and atopic dermatitis); autoimmune diseases (rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, and immune thrombocytopenic purpura); and inflammation of the lung (chronic obstructive pulmonary disease). See, e.g., Brian R. Wong et al., Expert Opin. Investig. Drugs (2004) 13(7):743-62; Sanderson et al. (2009); Jane Denyer & Vipul Patel, Drug News Perspective (2009) 22(3):146-50; Esteban S. Masuda & Jochen Schmitz, Pulmonary Pharmacology & Therapeutics (2008) 21:461-67; Malini Bajpai et al., Expert Opin. Investig. Drugs (2008) 17(5):641-59; and Anna Podolanczuk et al., Blood (2009) 113:3154-60. Other disorders include hematological malignancies, such as acute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-cell lymphoma (e.g., mantle cell lymphoma), and T-cell lymphoma (e.g., peripheral T-cell lymphoma); as well as epithelial cancers, such as lung cancer, pancreatic cancer, and colon cancer. See, e.g., Cynthia K. Hahn et al., Cancer Cell (2009) 16:281-294; D. H. Chu et al., Immunol. Rev. (1998) 165:167-180; A. L. Feldman et al., Leukemia (2008) 22:1139-43; A. Rinaldi et al., Br. J. Haematol. (2006) 132:303-316; B. Streubel et al., Leukemia (2006) 20:313-18; Maike Buchner et al., Cancer Research (2009) 69(13):5424-32; A. D. Baudot et al., Oncogene (2009) 28:3261-73; and Anurag Singh et al., Cancer Cell (2009) 15:489-500.
Various SYK inhibitors have been described in published patent applications. See, e.g., EP 1184376 A1; WO 01/83485 A1; WO 03/057695 A1; WO 2006/129100 A1; WO 01/09134 A1; WO 03/063794 A1; WO 2005/012294 A1; WO 2004/087699 A2; WO 2009/026107 A1; WO2009136995 A2; and WO2009/145856 A1.